Traditional ways in medicine to eliminate abnormal tissue or cells include surgery, chemotherapy, irradiation or combination of these. For radiation, both ionizing and non-ionizing types have been developed and successfully used for a range of abnormal tissues from overgrown blood vessels to pre-cancerous tissues to frank cancer. Ionizing radiation uses high energy particles enough to ionize atoms in a matter it passes through. It includes beta ray, x ray, gamma ray and neutron. Clinical application of ionizing radiation has been well developed to a point that it can be delivered to a specific area without damaging adjacent tissues, at a specific dose over a certain period of time to achieve a finite degree of tissue elimination in a consistent and reproducible way.
Thermal radiation belongs to non-ionizing radiation that includes infrared waves, microwaves and radiofrequency waves (Ref 1). Radiofrequency ablation uses resistive energy loss of tissue upon high frequency alternating electric current between 365 kHz and 550 kHz, delivered to longitudinal electrodes invasively inserted to a target tissue. Electric current passes from the longitudinal electrode to a electrically conductive pad attached to skin serving as a ground. The longitudinal electrode may have single or multiple probes and may be deployed through an introducer, as illustrated for an example in the U.S. Pat. Nos. 5,980,517 and 6,071,280. The generated resistive heat is proportionally dependent on the delivered radiofrequency energy and on intrinsic tissue properties such as heat conductivity and impedance. Drawbacks of the radiofrequency ablation include need of correct positioning of needle in the center of the target tissue, heat sink effect of adjacent blood vessels, small treatment volume, increasing impedance of the target tissue during therapy thereby progressively decreasing conductivity, inability to monitor temperature during therapy and occasional burn at a skin-to-ground transition site.
Microwave ablation operates between 915 MHz and 2.45 GHz, and electric field of microwave excites harmonic oscillations of water molecules in an alternating electric field. Other non-water molecules are heated by convection. Devices for microwave ablation comprise longitudinally insertable microwave antennas, as illustrated for an example in the U.S. Pat. Nos. 7,722,606 and 7,862,559, connected with a power and control unit via transmission cable. Microwave antenna emits electromagnetic radiation to tissue without an electric current, thereby avoiding problems of carbonization and tissue boiling. Compared to the radiofrequency ablation, microwave ablation may use multiple antennas at higher temperature covering a larger treatment volume without rising impedance. Yet temperature may not be monitored real-time during treatment. Size of a probe that houses antenna may be larger than that of radiofrequency probe, and selective heating of blood vessels may produce an increased risk of thrombosis of major blood vessels.
At near infrared, laser coagulation uses neodymium-yttrium aluminum garnet (Nd:YAG) laser light with a wavelength of 1064 nm. The laser produces monochromatic light and works independently of impedance rise that is associated with radiofrequency ablation. Success of laser coagulation depends on accurate delivery of laser optical fibers to a target area and real-time monitoring of therapy. Temperature may be monitored real-time and laser ablation may cover a larger treatment volume than radiofrequency ablation. Laser applicator is connected to a power and control unit via a coaxial sheath system, as illustrated in one example of the U.S. Pat. No. 7,344,529. Using a guidewire, a protective sheath should be positioned within or in the periphery of a target area before insertion of the laser applicator. The laser applicator needs to be inserted through the protective sheath to avoid direct contact with patient under computerized tomographic guidance. Ablation by laser then is monitored by magnetic resonance imaging. These multi-stage procedures increase chances of technical failure and also make the size of the sheath with applicator much larger than those of radiofrequency and of microwave ablation. Tissue carbonization may occur.
Hyperthermia with magnetic materials under alternating electromagnetic current was developed first in 1957 yet its widespread clinical use was hindered by technical limitations such as uncertain distribution of magnetic materials in a target area, need to place magnetic materials manually by needle injection or surgery, local tissue discomfort under high electromagnetic field strength due to the boundary effects, and difficulties in real-time monitoring of temperature and viability of the target area (Ref 2).
Despite these limitations, early clinical trials using thermoseeds of a pre-set Curie temperature embedded in tissue have been shown to be effective on enhancing killing of a few types of cancer such as brain cancer and prostate cancer, when used together with local radiation (Ref 3-4). Thermoseeds themselves could also retain radioactivity for combined potential for tissue ablation. For an example, the U.S. Pat. No. 6,497,647 proposes that cobalt combined with either palladum-103 or iodine-125 for ferromagnetic thermoseeds. These thermoseeds are usually paramagnetic, rod shaped and of millimeters in size. Main mechanism of heating of thermoseeds is Eddy current induced under alternating magnetic field that works on surface of the thermoseeds.
Further development of magnetic materials for hyperthermia produced multidomain ferromagnetic or ferrite particles, and ferromagnetic or superparamagnetic nanoparticles. Multidomain ferromagnetic particles are 1-300 μm in size and generate heat by a mechanism of hysteresis loss under alternating magnetic field. Ferromagnetic or superparamagnetic nanoparticles are 1-100 nm in size and generate heat mainly by Brownian and Neel relaxation processes (Ref. 5-6). Heating of a target tissue depends on specific absorption rate of an implanted magnetic material in an alternating magnetic field. Thermal energy is released to surrounding tissue as a result of physical processes that differ according to size of the magnetic material used and strength of the applied magnetic field (Ref 7). In an effort to enhance specificity to certain tissue, magnetic nanoparticles have been combined with antibody against tumor specific proteins such as Her-2/neu, and have been successfully localized to the target tissue (Ref 8). In another application, superparamagnetic iron oxide nanoparticles have been developed for hyperthermia albeit clinical benefit of hyperthermia using the iron oxide nanoparticles needs to be confirmed (Ref 9-10). Examples of these materials are described in the U.S. Pat. Nos. 6,541,039, 6,979,466, 7,074,175, 7,731,648, 7,842,281 and 7,951,061.
Hyperthermia by alternating magnetic field is limited by lack of specific localization of magnetic materials to a target area in a consistent and verifiable way; by need to introduce magnetic materials into a target area by surgery or direct injection oftentimes; by inhomogeneity of temperature distribution in the target area; by lack of real-time monitoring of temperature and effectiveness of tissue death; by nonspecific uptake of magnetic materials, especially of nanoparticles, by normal tissues of body such as macrophages and monocytes of the reticuloendothelial system, which may induce unwanted heating of normal tissues (Ref 11); by potentially high concentration of dissolved magnetic materials in blood such as iron oxide, which may cause toxicity; by the boundary effects by externally applied high strength magnetic field between tissues of different dielectric constant and conductivity (Ref 2); by increase in Eddy current density at skin level especially in folds under externally applied magnetic field (Ref 2); by lack of adequate means to deliver both alternating magnetic current and magnetic materials to a thin-walled body structure such as bowels, pleural or abdominal cavity.